Cyclin E is over-expressed and present in low molecular weight (LMW) isoforms in selected breast cancer cells and tumor tissues. We evaluated the prognostic potential of the LMW isoforms of cyclin E in a retrospective study of 395 patients with breast cancer and found that the LMW isoforms are more powerful predictors of poor outcome than estrogen- and progesterone-receptor status or levels of cyclin D1, cyclin D3, and HER2/neu. Our preliminary findings suggest that deregulation of cyclin E alters sensititivity of breast cancers to anti-estrogens and chemotherapeutic agents, suggesting that cyclin E may also be predictor of poor response to chemotherapy. We hypothesize that cyclin E is a surrogate marker for prognosis and response to systemic therapy;further, because cyclin E has a major role in cell cycle progression, we hypothesize that it is a novel target for therapy. Thus, the overall goal of the proposed work is to establish the value of cyclin E in predicting prognosis and response to therapy in patients with breast cancer and begin to investigate cyclin E as a target for therapy;to achieve this goal, we will address the following specific aims: 1. Establish cyclin E as a prognostic marker and a predictor of clinical response to neoadjuvant chemotherapy and adjuvant hormonal therapy in patients with stage II and III breast cancer 2. Determine the mechanisms of reduced sensitivity to chemotherapy and hormonal therapy in cyclin E overexpressing breast cancer cells 3. Identify cyclin E/cyclin-dependent kinase 2 (CDK2) inhibitors that selectively target the activity of the LMW forms of cyclin E and investigate the effect of these inhibitors on growth and progression of breast cancer in vitro and in vivo Development of cyclin E as a predictor of response to systemic therapy will allow for better .selection of patients for systemic treatment. Patients with breast cancer whose tumors express the LMW forms of cyclin E have a propensity to develop metastatic disease, and we anticipate that inhibition of the hyperactive LMW cyclin E-CDK2 kinase complex will represent a novel treatment strategy for this patient: population.